TNBC Advances Feature Immunotherapy, PARP Inhibitors, and ADCs

Kari B. Wisinski, MD

The roles of immunotherapy, antibody-drug conjugates (ADCs), and PARP inhibitors have been well established in the triple-negative breast cancer (TNBC) paradigm, said Kari B. Wisinski, MD, who added that ongoing research efforts are now expanding those roles by looking at the treatment modalities in other settings and for specific subtypes within TNBC.

“Immunotherapy looks promising in the early-stage TNBC setting. There are times now that we could consider it for patient care in today’s world, even though it is not in the [National Comprehensive Cancer Network] guidelines yet,” said Wisinski. “[Additionally], we are starting to see a role for PARP inhibitors outside of germline BRCA mutation carriers. We’ll watch the data as it comes out over time, but it is exciting to see.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on breast cancer, Wisinski, a medical oncologist at the University of Wisconsin Carbone Cancer Center and UW Health, a member of the UW Health Breast Center, and an associate professor of hematology/oncology in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health, discussed the evolving roles of immunotherapy, ADCs, and PARP inhibitors in TNBC.

OncLive®: With regard to the efficacy of immunotherapy in the early-stage setting, what was learned from the NeoTRIP trial?

Wisinski: NeoTRIP was a phase 3 study in the context of neoadjuvant treatment for TNBC. All patients received carboplatin and taxane-based chemotherapy and then went on to have surgery. Patients received anthracyclines following surgery. Patients were then randomized to get atezolizumab [Tecentriq] or no atezolizumab.

The primary end point was event-free survival [EFS], which has not been reported yet. However, a key secondary end point was pathologic complete response [pCR], which was not improved with the addition of atezolizumab to chemotherapy.

Also, the addition of atezolizumab did not appear to significantly increase chemotherapy toxicity. There were higher rates of transaminitis or liver function abnormalities in this study, but not a lot of significant effects on chemotherapy toxicity. Immune-mediated toxicities were kind of anticipated events with what we see with these agents across studies. Grade 3 and 4 adverse effects were really pretty rare.

How are these data being interpreted among other findings that have emerged in this space?

It is important to put this in context with 2 other studies. One is KEYNOTE-522, [which evaluated] the addition of pembrolizumab [Keytruda] to [paclitaxel and carboplatin followed by doxorubicin or epirubicin and cyclophosphamide]. Again, this study looked at pCR as the primary end point, but also EFS as a co-primary end point. Those findings have been reported previously and showed an improvement in pCR, as well as an early look at improvement in EFS. We are waiting for follow-up studies on that.

A third study, IMpassion031, was presented at the 2020 ESMO Virtual Congress with atezolizumab and also showed some improvement in pCR with the addition of atezolizumab to chemotherapy. Again, the chemotherapy regimen included anthracycline.

Putting all 3 of these studies together, we have 2 that have been positive in terms of pCR. Both of those trials included an anthracycline-based regimen with the neoadjuvant chemotherapy backbone. Conversely, the one negative study, NeoTRIP, did not have an anthracycline in the backbone.

Whether that is the true reason for the differences between these studies [is unknown]. Are there other characteristics that are different between these patient populations? We don’t know yet. It’s exciting though to see the emergence of immunotherapy for TNBC in the early-stage setting. We’ll continue to follow these data over time, but it [appears to be] a new emerging treatment.

Shifting to ADCs, sacituzumab govitecan (Trodelvy) is now a standard of care for patients with metastatic TNBC. How have the data from the confirmatory ASCENT trial added to our knowledge of the agent?

Sacituzumab govitecan is an ADC that targets Trop-2 on epithelial cells. Trop-2 is common in many different types of cancer, including TNBC. [A humanized IgG antibody targeted against Trop-2] is linked to an SN-38 compound, which is an irinotecan-based chemotherapy compound. The linker molecule [consists of] many different molecules of SN-38, so [the drug has] higher potency.

A prior phase 2 study suggested high response rates and good tolerability [with sacituzumab govitecan]. Those findings led to the ASCENT study, which was presented at ESMO [2020]. ASCENT was a randomized phase 3 study of sacituzumab govitecan vs physician’s choice of chemotherapy. [Sacituzumab govitecan] is for patients who are in later lines of therapy and have had several previous lines of therapy. In the trial, patients had to have had 2 prior lines of chemotherapy in the metastatic setting.

The ASCENT study demonstrated a clear benefit in progression-free survival [PFS] and overall survival [OS] with sacituzumab govitecan compared with physician’s choice of chemotherapy.

The emergence of PARP inhibitors has also been transformative. What research efforts are underway to expand the utility of these agents in TNBC?

Some other agents and other combinations are of interest. The previous data in germline BRCA-mutant advanced breast cancer, including TNBC, demonstrated that PARP inhibitors had an improved PFS and response rate compared with standard chemotherapy. However, no difference in OS [was observed] in those studies.

It’s important to watch for different combinations that are coming out with the PARP inhibitors, as well as potentially new DNA damage repair [DDR] pathway–targeted agents. Some interesting early data [have emerged] with combinations of PARP inhibitors and immunotherapy [showing] some nice, durable response rates. We will see if that pans out in TNBC.

Have PARP inhibitors demonstrated improved responses among patients with other DDR pathway gene mutations?

The other study that is related to TNBC, though somewhat tangentially, relates to the PARP inhibitor olaparib [Lynparza]. This study was presented at [the 2020 ASCO Virtual Scientific Program] and looked at the role of olaparib in women with HER2-negative breast cancer and a germline alteration in another DDR pathway, such as PALB2, CHEK2, ATM, or a somatic tumor mutation without a germline BRCA1/2 mutation or [another DDR pathway mutation].

Of the 2 cohorts, the first [included the patients with] the germline mutations other than BRCA. [Olaparib] demonstrated a high response rate and the trial met its primary end point. In particular, patients with a germline PALB2 mutation had an 80% response rate with olaparib. If we look at the somatic mutation cohort, patients with a somatic BRCA1/2 mutation had a 50% response rate.

The ATM and CHEK2 cohorts did not look like they had much response, but these were small numbers. It was exciting to see that PARP inhibitors may have a role beyond BRCA2 germline mutation carriers.

What other emerging agents appear promising in the TNBC space?

The other group of agents that are interesting are the AKT inhibitors. We’ve seen 2 randomized phase 2 studies, LOTUS and PAKT, with AKT inhibitors in combination with taxanes. Both trials demonstrated some improvement in PFS with hints toward improvement in OS, in advanced TNBC. [The results also showed] some suggestion that PTEN loss or a PI3K-altered pathway [could be] a biomarker [to predict] who is going to benefit the most [AKT inhibitors].